6,11-Dihydrodibenzo-thiepin-11-ones, compositions and uses thereof

ABSTRACT

This invention relates to novel 6,11-dihydrodibenzo[b.e.]-thiepin-11-ones, methods of preparation, compositions and uses thereof.

This application is a continuation-in-part of U.S. application Ser. No.550,316, filed Feb. 18, 1975 and U.S. application Ser. No. 591,725,filed June 30, 1975, both now abandoned, said U.S. application Ser. No.591,725 also being a continuation-in-part of said U.S. application Ser.No. 550,316.

DESCRIPTION OF THE INVENTION

This invention relates to novel 6,11 -dihydrodibenzo-[b.e.]-thiepin-11-ones selected from the group consisting of those having the formulas:##STR1## or the individual (d)-acid isomer or (l)-acid isomer of Formula(B), wherein R is hydrogen, an alkyl group containing from one to 12carbon atoms, or a pharmaceutically acceptable salt thereof when R ishydrogen, or the said esters and pharmaceutically acceptable salts ofthe individual isomers of Formula B, and methods for the preparationthereof.

Also included in this invention are compositions and methods of use forthe compounds of Formulas (A), (B), or the (d)-acid isomer of Formula(B), or the said esters and pharmaceutically acceptable salts of the(d)-acid isomer.

The term "alkyl" refers to and includes branched and straight chainhydrocarbons containing from one to 12 carbon atoms. Typical alkylgroups include methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl,isoamyl, neopentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, 6-methyldecyl, dodecyl, and the like.

The term "pharmaceutically acceptable salts" refers to salts preparedfrom pharmaceutically acceptable non-toxic bases including inorganicbases and organic bases. Salts derived from inorganic bases includesodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, zinc,copper, manganous, aluminum, ferric, manganic salts and the like.Particularly preferred are the ammonia, potassium, sodium, calcium andmagnesium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, substituted amines including naturally occurring substitutedamines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2 -dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like.Particularly preferred organic non-toxic bases are isopropylamine,diethylamine, ethanolamine, piperidine, tromethamine, choline andcaffeine.

The novel compounds of Formula (B), and Formulas (10), (11), (12) and(14) depicted below exist as pairs of optical isomers (orenantiomorphs), i.e., a (dl) mixture. However, each optical isomer aswell as the (dl) mixtures thereof are included within the presentinvention.

When the novel compounds of this invention are to be used to elicite aphysiological response (e.g., anti-inflammatory, analgesic andanti-pyretic activity), i.e., they are to be used as medicinals, apreferred sub-grouping is that of the compounds of Formulas (A) and (B),and the (d)-acid isomer of Formula (B) and the esters andpharmaceutically acceptable salts thereof.

A still further sub-grouping, for compounds to be used as medicinals arethe compounds of Formula (B) and the (d)-acid isomer of Formula (B) andthe esters and pharmaceutically acceptable salts thereof, and thissub-grouping may be divided into two further sub-groupings made up of(a) the compounds of Formula (B), i.e., the (dl)-compounds and (b) the(d)-acid isomer of Formula (B) and the esters and pharmaceuticallyacceptable salts thereof. The (l)-acid isomer of Formula (B) and theesters and pharmaceutically acceptable salts thereof are useful asintermediates for the preparation of the (dl)-acid of Formula (B), asdescribed more fully below.

Japanese Patent Publication No. 425/72, published Jan. 7, 1972, broadlydiscloses compounds of the formula: ##STR2## [wherein R₁ , R₂ and R₃ areeach a hydrogen atom or a lower alkyl group (e.g. methyl, ethyl, propyland isopropyl); X is a hydrogen atom, a halogen atom (Cl, Br, I and F)or a lower alkyl group; and Y is an oxygen atom, --CH₂ S -- , or##STR3## (wherein R₄ is a hydrogen atom or a lower alkyl group)] or thesalt thereof; and specifically names in Example 3 thereof 11 -oxo-6,11-dihydro-dibenzo[ b.e.] thiepin-2 -yl-acetic acid.

German OLS 24 42 060 , laid open May 7, 1975, broadly discloses oxepincompounds of the formula: ##STR4## wherein X is C=0, CHCl, CHBr, CH₂ ,or CHOR⁴ ; Y is alkyl of from 1 to 4 carbon atoms, alkoxy of from 1 to 4carbon atoms, halogen or trifluoromethyl; n is an integer 0, 1, 2 or 3 ;Z is COOR⁵ , CH₂ OR⁵ , CONR₂ ⁵ or CONHOR⁵ ; and R¹ to R⁵ are hydrogen,or alkyl of from 1 to 4 carbon atoms.

Certain oxepin compounds are also disclosed in Belgian Pat. No. 818,055,laid open Nov. 18, 1974.

The novel compounds of my invention, namely, the compounds of Formulas(A) and (B), and the d-acid isomer of Formula (B) and the esters andpharmaceutically acceptable salts thereof, have markedly superioranti-inflammatory activity when compared with the closest prior artcompounds of the Japanese patent (namely, 11 -oxo-6,11 -dihydrodibenzo[b.e.] thiepin-2 -yl-acetic acid and 11 -oxo-6,11 -dihydrodibenzo[ b.e.]thiepin-2 -yl-propionic acid), using the carragenin rat paw assay (theassay referred to in the Japanese patent), as shown below.

The novel compounds of this invention are prepared according to thereaction scheme outlined in the flow sheets which follow: ##STR5##

Diisopropyl nitroterephthalate (1) is prepared by esterifyingnitroterephthalic acid (a) with isopropanol, the isopropanol servingboth as reactant and solvent, in the presence of hydrogen chloride at atemperature of from about 25° C. to the reflux temperature of thereaction mixture for from about 48 to about 200 hours. Ordinarily, it ispreferred to carry out the reaction at reflux for from about 48 to about96 hours.

Diisopropyl nitroterepthalate (1) is then treated with benzyl mercaptanand sodium hydride in the presence of a suitable organic solvent, e.g.,dimethylformamide, dimethylsulfoxide, and the like, at temperature offrom about -40° C. to about 50° C., preferably, from about -35° C. toabout 20° C., for from about 1 hour to about 10 hours preferably fromabout 2 hours to about 3 hours, to obtaindiisopropyl-(benzylthio)-terephthalate (2).

Base hydrolysis of (2) yields (benzylthio)-terephthalic acid (3). Thisreaction is carried out by treating (2) with a base, e.g., potassiumhydroxide, sodium hydroxide, and the like, in the presence of water, andan organic solvent, e.g., methanol, ethanol, propanol, and the like, ata temperature of from about 40° C. to the reflux temperature of thereaction mixture, for from about 1 to about 12 hours. Preferably thehydrolysis reaction is carried out using aqueous methanolic potassiumhydroxide at reflux temperature.

(Benzylthio)-terephthalyl chloride (4) is obtained by treating (3) withthionyl chloride at a temperature of from about 25° C. to the refluxtemperature of the reaction mixture for about 1 to about 6 hours. It ispreferred to carry out this reaction at reflux temperature.

The cyclization reaction by which (4) is converted to 6,11-dihydrodibenzo-[b.e.]-thiepin-11 -one-3 -carbonyl chloride (5) iscarried out by treating 4) with nitromethane and aluminum chloride inthe presence of a suitable organic solvent, e.g., methylene chloride,carbon disulfide, o-dichlorobenzene, and the like, at a temperature offrom about 15° to about 35° C. for from about 1/2 to about 24 hours,preferably at from about 20° to about 25° C., for from about 4 to about12 hours. The preferred solvent is methylene chloride.

The conversion of (5) to 3 -diazoacetyl-6,11-dihydrodibenzo-[b.e.]-thiepin-11 -one (6) is carried out by treating(5) with diazomethane, in an organic solvent, e.g., methylene chloride,ether, carbon tetrachloride, and the like, or mixtures thereof, at atemperature of from about -20° to about 10° C., for from about 15minutes to about 12 hours. Preferably this reaction is carried out at atemperature of from about -5° to about 5° C. for from about 15 to about60 minutes.

The rearrangement of (6) to methyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11 -one-3 -acetate (7) is carried out byintimately mixing (6) with methanol at a temperature of from about 50°C. to the reflux temperature of the mixture, followed by the addition,in portions, of a silver salt, e.g., silver benzoate, dissolved orsuspended in a solvent, e.g., methanol or triethylamine. Likewise, other3 -esters, otherwise corresponding to (7) are obtained by substitutingthe appropriate alkyl alcohol, containing 2 to 12 carbon atoms, formethanol.

The hydrolysis of (7) to 6,11 -dihydrodibenzo-[b.e.]-thiepin-11 -one-3-acetic acid (8) is carried out by treating (7) with a base, e.g.,potassium hydroxide, sodium hydroxide, sodium carbonate, and the like,in the presence of water and an organic solvent, e.g., methanol,ethanol, propanol, and the like, at a temperature of from about 0° toabout 70° C. for from about 1 to about 24 hours. This hydrolysisreaction is preferably carried out using aqueous methanolic potassiumhydroxide at a temperature of from about 20° to about 30° C. Likewisethe other 3 -esters, obtained as described above, are hydrolyzed to the3 -acetic acid (8). The temperature for the hydrolysis will depend onthe particular ester to be hydrolyzed and thus can range from about 0°C. to reflux.

Treatment of 6,11 -dihydrodibenzo-[b.e.]-thiepin-11 -one-3 -carbonylchloride (5) with diazoethane in an organic solvent, e.g., ether,methylene chloride, carbon tetrachloride, and the like, at a temperatureof from about -30° to about -10° C. is productive of 3-(α-diazopropionyl)-6,11 -dihydrodibenzo-[b.e.]-thiepin-11 -one (9). Itis preferred to carry out this reaction using ethereal diazoethane at atemperature of from about -25° to about -20° C.

The rearrangement of (9) to benzyl (dl)-2 -(6,11-dihydrodibenzo-[b.e.]-thiepin-11 -one-3 -yl) propionate (10) is carriedout by treating (9) with a high boiling alcohol, e.g., benzyl alcohol,in the presence of an organic amine, e.g., collidine, quinoline,diethylaniline, and the like, at a temperature of from about 160° toabout 190° C., for about 1 minute to about 1 hour, preferably from about170° to about 175° C. for from about 2 to about 30 minutes.

To aid in the obtention of the free acid, (dl)-2 -(6,11-dihydrodibenzo-[b.e.]-thiepin-11 -one-3 -yl) propionic acid (12), inpurer form, (10) is first subjected to base hydrolysis as previouslydescribed above for the conversion of (7) to (8) [or (2) to (3)] ,followed by treatment with dicyclohexylamine to obtaindicyclohexylammonium (dl)-2 -(6,11 -dihydrodibenzo-[b.e.]-thiepin-11-one-3 -yl) propionate (11).

The conversion of (11) to (dl)-2 -(6,11-dihydrodibenzo-[b.e.]-thiepin-11 -one-3 -yl) propionic acid (12) iscarried out by treating (11) in an organic solvent, e.g., methylenechloride, ether, benzene, and the like, with an acid salt or strongacid, e.g., sodium acid sulfate, hydrochloric acid, sulfuric acid, andthe like, at a temperature of from about 0° to about 50° C., for fromabout 1 minute to about 1 hour, preferably from about 20° to about 25°C., for from about 1 to about 5 minutes.

Alternatively the compounds of Formula (12) are prepared as outlined inthe following reaction scheme: ##STR6## wherein R' is an alkyl groupcontaining from 1 to 12 carbon atoms.

The α -methylation of the compounds of Formula (13), the esters of 6,11-dihydrodibenzo-[b.e.]-thiepin-11 -one-3 -acetic acid (R'=alkyl of C₁-C₁₂ , preferably R'=methyl), to obtain the compounds of Formula (14),the esters of (dl)-2 -(6,11 -dihydrodibenzo-[b.e.]-thiepin-11 -one-3-yl) propionic acid (R'= alkyl C₁ -C₁₂ , preferably R'=methyl), iscarried out by treating the compounds of Formula (13) with an alkalimetal hydride, alkali metal amide, alkali metal dialkylamide, and thelike, such as sodium hydride, lithium diisopropylamide or sodiumdimethylamide, in the presence of a polar non-protic solvent, e.g.,N,N-dimethylacetamide, dimethylformamide, hexamethylphosphoric triamide(HMPA), dimethylsulfoxide, sulfolane, and the like, at a temperature offrom about 10° C. to about 60° C., followed by treatment with a methylhalide, e.g., methyl iodide, or a dialkyl sulfate, e.g., dimethylsulfate, at a temperature of from about -15° to about 60° C., for fromabout 5 minutes to about 1 hour.

The compounds of Formula (14) are then hydrolyzed to the free acids ofFormula (12), according to the method described above for the hydrolysisof the compound of Formula (7) to Formula (8).

Methods for the preparation of the compounds of Formula (13), wherein R'is C₂ -C₁₂ alkyl are described fully below.

The (dl) mixture of (12) is separated into its respective d-isomer,(12)-(d)-acid isomer, and 1 -isomer, (12 )-(l)-acid isomer, according totechniques known in the art, e.g., the resolution techniques set forthin Example 12 B below.

Upon their preparation, the free acids of Formulas (8), (12),(12)-(d)-acid isomer and (12)-(l)-acid isomer, can be converted to theircorresponding esters and acid addition salts.

The salt derivatives of the compounds of Formulas (8), (12),(12)-(d)-acid isomer, and (12)-(l)-acid isomer, are prepared by treatingthese free acids with an appropriate amount of a pharmaceuticallyacceptable base. Representative pharmaceutically acceptable bases aresodium hydroxide, potassium hydroxide, lithium hydroxide, ammoniumhydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide,zinc hydroxide, copper hydroxide, manganous hydroxide, aluminumhydroxide, ferric hydroxide, manganic hydroxide, isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2 -dimethylaminoethanol, 2 -diethylaminoethanol,tromethamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. The reaction isconducted in water, alone or in combination with an inert,water-miscible organic solvent, at a temperature of from about ° toabout 100° C., preferably at room temperature. Typical inert,water-miscible organic solvents include methanol, ethanol, isopropanol,butanol, acetone, dioxane or tetrahydrofuran. The molar ratio ofcompounds of Formulas (8), (12), (12)-(d)-acid isomer and(12)-(l)-acid-isomer, to base used are chosen to provide the ratiodesired for any particular salt. For preparing, for example, the calciumsalts or magnesium salts of the compounds of Formulas (A) and (B), andthe individual (d)- and (1)-acid isomers of the latter, the free acidstarting material of Formulas (8) (12), (12)-(d)-acid isomer and(12)-(l)-acid isomer, respectively, can be treated with at leastone-half molar equivalent of pharmaceutically acceptable base to yield aneutral salt. When the aluminum salts of the compounds of Formulas (A)and (B), and the individual (d)- and (l)-acid isomers of the latter, areprepared, at least one-third molar equivalent of the pharmaceuticallyacceptable base are employed if a neutral salt product is desired.

In the preferred procedure, the calcium salts and magnesium salts of thecompounds of Formulas (A) and (B), and the calcium and magnesium saltsof the (d)- and (l)-acid isomers of Formula (B) can be prepared bytreating the corresponding sodium or potassium salts of the compound ofFormulas (A) and (B), and the sodium or potassium salts of the (d)- and(l)-acid isomers of Formula (B), with at least one-half molar equivalentof calcium chloride or magnesium chloride, respectively, in an aqueoussolution, alone or in combination with an inert water-miscible organicsolvent, at a temperature of from about 20° to about 100° C. Preferably,the aluminum salt of the compounds of Formulas (A) and (B), and thealuminum salt of the (d)- and (l)-acid isomers of Formula (B), can beprepared by treating the corresponding free acids of the compounds ofFormulas (8), (12), (12)-(d)-isomer and (12)-(l)-isomer with at leastone-third molar equivalent of an aluminum alkoxide, such as aluminumtriethoxide, aluminum tripropoxide and the like, in a hydrocarbonsolvent, such as benzene, xylene, cyclohexane, and the like at atemperature of from 20° to about 115° C. Similar procedures can be usedto prepare salts of inorganic bases which are not sufficiently solublefor easy reaction.

The salt products are isolated by conventional means. For example, thereaction mixtures are evaporated to dryness, and the salts can befurther purified by conventional methods.

The salt derivatives of the compounds of Formulas (8), (12) and the saltderivatives of 12-(d)-acid isomer and 12-(l)-acid isomer, can bereconverted to their respective free acids by acidifying said salts withan acid, preferably an inorganic acid, e.g., hydrochloric acid, sulfuricacid, and the like, at temperature of from about 0° to about 30° C.,preferably at room temperature.

The esters of Formulas (A) and (B), and the esters of the (d)-acidisomer and (l)-acid isomer of Formula (B), are prepared by esterifyingthe corresponding free acids of Formulas (8), (12), (12)-(d)-acid isomerand (12)-(l)-acid isomer, with an alcohol reagent corresponding to thedesired ester, e.g., an alkanol having up to 12 carbon atoms. Thisreaction is conducted in the presence of a strong acid, such as borontrifluoride, hydrogen chloride, sulfuric acid, p-toluenesulfonic acid,and the like. If the alcohol reagent used in the esterification is aliquid at the reaction temperature, the alcohol reagent can be thereaction solvent. Optionally, the reaction can be carried out in aninert organic solvent in which the free acids of Formulas (8), (12),(12)-(d)-acid isomer and (12)-(l)-acid isomer, and the alcohol reagentare soluble, such as a hydrocarbon solvent, e.g., hexane, iso-octane,decane, cyclohexane, benzene, toluene, xylene; a halogenated hydrocarbonsolvent, e.g., methylene chloride, chloroform, dichloroethane; or anether solvent, e.g., diethyl ether, dibutyl ether, dioxane,tetrahydrofuran; and the like. In the case where the alcohol reagent isa solid, the reaction preferably is conducted in a non-aqueous liquidinert organic solvent. The reaction is conducted at from about 0° C. tothe reflux temperature of the reaction mixture, preferably usinghydrogen chloride at a temperature of from 15° to about 35° C.

The product is isolated by conventional means such as diluting thereaction mixture with water, extracting the resulting aqueous mixturewith a water-immiscible inert organic solvent, such as diethyl ether,benzene, methylene chloride, and the like, combining the extracts,washing the extracts with water to neutrality and then evaporating underreduced pressure.

The preferred acid esters of Formulas (A) and (B), and the esters of the(d)-acid isomer and (l)-acid isomer of Formula (B), are those esterderivatives prepared from methyl alcohol, ethyl alcohol, propyl alcohol,isopropyl alcohol, butyl alcohol, 2-butyl alcohol, isoamyl alcohol,pentyl alcohol, 2-pentyl alcohol, isopentyl alcohol, hexyl alcohol,2-hexyl alcohol, isohexyl alcohol, heptyl alcohol, 2-heptyl alcohol,isoheptyl alcohol, octyl alcohol, 2-octyl alcohol, isooctyl alcohol,nonyl alcohol, 2-nonyl alcohol, isononyl alcohol, decyl alcohol, 2-decylalcohol, isodecyl alcohol, undecyl alcohol, dodecyl alcohol, and thelike.

Alternatively, the esters of Formulas (A) and (B), and the esters of the(d)-acid isomer and (l)-acid isomer of Formula (B), can be prepared bytransesterification, according to methods known in the art. It ispreferred in preparing the esters via transesterification to go from alower ester to a higher ester, e.g., from the methyl ester, for example,to the isoamyl ester, for example. However, by using a substantialexcess of a lower alcohol, a higher ester can be transesterified to alower ester; thus, for example, by using a substantial excess ofethanol, the hexyl ester is converted by the transesterification to theethyl ester.

The (12)-(l)-acid isomer,(l)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3yl) propionic acid,and the corresponding esters and salts thereof, are converted to(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid(12) by treatment with an excess of a strong base, e.g., sodiumhydroxide, potassium hydroxide, tetramethylammonium hydroxide, and thelike, at a temperature of from about 60° C. to the reflux temperature ofthe reaction mixture for from about 4 to about 10 hours, under an inertatmosphere, e.g., nitrogen, followed by acidification with a mineralacid, e.g., hydrochloric acid, sulfuric acid, and the like. When theabove reaction is carried out on the (12)-(l)-acid isomer or saltsthereof, water is the preferred solvent. When the reaction is carriedout on the esters of the (12)-(l)-acid isomer the preferred solvent isan aqueous alkanol, e.g., aqueous methanol.

The compounds of Formulas (A) and (B), and the (d)-acid isomer ofFormula (B) and the esters and pharmaceutically acceptable saltsthereof, are useful as anti-inflammatory agents, platelet aggregationinhibitors, fibrinolytic agents, and as smooth muscle relaxants. Thecompounds of Formulas (A) and (B), and the (d)-acid isomer of Formula(B) and the esters and pharmaceutically acceptable salts thereof, can beused both prophylactically and therapeutically.

The compounds of Formulas (A) and (B), and the (d)-acid isomer ofFormula (B) and the esters and pharmaceutically acceptable saltsthereof, exhibit anti-inflammatory, analgesic and anti-pyreticactivities. Accordingly, the compositions containing these compounds areuseful in the treatment and elimination of inflammation such asinflammatory conditions of the muscular skeletal system, skeletal jointsand other tissues, for example, in the treatment of inflammatoryconditions such as rheumatism, concussion, laceration, arthritis, bonefractures, post-traumatic conditions, and gout. In those cases in whichthe above conditions include pain and pyrexia coupled with inflammation,the instant compounds are useful for the relief of these conditions aswell as the inflammation.

Administration of the active compound of Formula (A) and (B), and the(d)-acid isomer of Formula (B) and the esters and pharmaceuticallyacceptable salts thereof, in an appropriate pharmaceutical compositioncan be via any of the accepted modes of administration of agents for thetreatment of inflammation, pain, or pyrexia, or the prophylaxis thereof.Thus, administration can be for example, orally, parenterally, ortopically, in the form of solid, semi-solid or liquid dosage forms, suchas, for example, tablets, suppositories, pills, capsules, powders,liquids, suspensions, creams, lotions, ointments, or the like,preferably in unit dosage forms suitable for simple administration ofprecise dosages. The compositions will include a conventionalpharmaceutical carrier or excipient and an active compound of Formulas(A) or (B), or the (d)-acid isomer of Formula (B) and the esters andpharmaceutically acceptable salts thereof, and, in addition, may includeother medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.

The preferred manner of administration, for the conditions detailedabove, is oral using a convenient daily dosage regimen which can beadjusted according to the degree of affliction. Generally, a daily doseof from 0.05 mg. to 10 mg. of the active compound of Formulas (A) and(B), and the (d)-acid isomer of Formula (B) and the esters andpharmaceutically acceptable salts thereof, per kilogram of body weightis used. Most conditions respond to treatment comprising a dosage levelof the order of 0.25 mg. to 3 mg. per kilogram of body weight per day.For such oral administration, a pharmaceutically acceptable non-toxiccomposition is formed by the incorporation of any of the normallyemployed excipients, such as, for example, pharmaceutical grades ofmannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum,cellulose, glucose, sucrose, magnesium carbonate, and the like. Suchcompositions take the form of solutions, suspensions, tablets, pills,capsules, powders, sustained release formulations and the like.

The active compound of Formulas (A) and (B), and the (d)-acid isomer ofFormula (B) and the esters and pharmaceutically acceptable saltsthereof, may be formulated into a suppository using, for example,polyalkylene glycols, for example, polypropylene glycol, as the carrier.Liquid pharmaceutically administerable compositions can, for example, beprepared by dissolving, dispersing, etc. an active compound, asdescribed above, and optional pharmaceutical adjuvants in a carrier,such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form a solution or suspension. Ifdesired, the pharmaceutical composition to be administered may alsocontain minor amount of non-toxic auxiliary substances such as wettingor emulsifying agents, pH buffering agents and the like, such as forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleate,etc.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania,14th Edition, 1970. The composition to be administered will, in anyevent, contain a quantity of the active compound(s) in apharmaceutically effective amount for relief of the particular conditionbeing treated in accordance with the teachings of this invention.

The compounds of Formulas (A) and (B), and the (d)-acid isomer ofFormula (B) and the esters and pharmaceutically acceptable saltsthereof, described above, are also uterine smooth muscle relaxants andthus are useful as agents for maintaining the pregnancy of pregnantmammals, for the benefit of the mother and/or the fetus, untiltermination of the pregnancy is considered, from a medical point ofview, to be favorable, or more favorable, for the mother and/or thefetus. It should be understood, however, that in certain instances, forexample where parturition has already begun (i.e., the mother isexperiencing uterine contractions, especially near full term), thatadministration of the compounds herein described may not maintain thepregnant state for an indefinite period of time. Rather, in suchinstances, the pregnancy will, most probably, be slightly "prolonged", afactor which may be advantageous to either the mother and/or the fetus.

In particular, the compounds of Formulas (A) and (B), and the (d)-acidisomer of Formula (B) and the esters and pharmaceutically acceptablesalts thereof, are used as agents for delaying the onset of, or forpostponing, parturition. As used in this application, the phrase "todelay the onset of parturition" is intended to cover that delay inparturition caused by the administration of the compounds of Formulas(A) and (B), and the (d)-acid isomer of Formula (B) and the esters andpharmaceutically acceptable salts thereof, at any time before uterinemuscle contractions have begun. Thus, it is intended that theaforementioned phrase cover abortion prevention early in pregnancy(i.e., before the fetus is "viable") as well as delaying prematureparturition, a term which sometimes is used with reference to thatpremature labor experienced later in the pregnancy when the fetus isconsidered to be "viable". In either case, the agents are administeredas prophylactic agents in that such administration tends to prevent theonset of parturition. This administration is particularly useful in thetreatment of women having a history of spontaneous abortion, miscarriageor premature delivery (i.e., delivery prior to full term). Suchadministration is also useful where there are clinical indications thatthe pregnancy might be terminated prior to that time and is consideredfavorable to the mother and/or fetus.

With respect to animals, this treatment can also be utilized tosynchronize the deliveries from a group of pregnant animals to happen ator about the same time, or to happen at or about a desired time and/orplace, when the births can be handled with greater facility.

As used in this application, the phrase "postponing parturition" isintended to cover that delay in parturition caused by the administrationof the compounds of Formulas (A) and (B), and the (d)-acid isomer ofFormula (B) and the esters and pharmaceutically acceptable salts thereofafter uterine muscle contractions have begun. The condition of thepatient, including the time within the gestation period when thecontractions have begun, the severity of the contractions and how longthe contractions have taken place will affect the results achieved withthe administration of the compounds of Formulas (A) and (B), and the(d)-acid isomer of Formula (B) and the esters and pharmaceuticallyacceptable salts thereof. For example, the effect can be to reduce theintensity and/or the duration of the contractions (the actual act ofparturition being "prolonged"), or to stop the contractions altogether.In either case, the effect will be to prolong the gestation periodalthough, depending upon the condition of the patient as describedabove, the effect may either be slight or, under appropriatecircumstances, somewhat greater. Such administration may be to preventspontaneous abortion, to cause the delivery to be more easilyaccomplished and/or less painful to the mother, or to occur at a moreappropriate time and/or place.

In all cases, administration of the compounds of Formulas (A) and (B),and the (d)-acid isomer of Formula (B) and the esters andpharmaceutically acceptable salts thereof, for the purposes set forthherein, should be consistent with best and/or accepted medical (orveterinary) practices so as to maximize the benefits to the mother andthe fetus. For example, administration should not be continued so longpast full term that the fetus dies in utero.

In the practice of the methods of the present invention, atherapeutically effective amount of a compound of Formulas (A) and (B),and the (d)-acid isomer of Formula (B) and the esters andpharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition containing a compound of Formulas (A) and (B), and the(d)-acid isomer of Formula (B) and the esters and pharmaceuticallyacceptable salts thereof, is administered to the pregnant mammal via anyof the usual and acceptable methods known in the art. The compound canbe administered either singly or in combination with another compound orcompounds, as defined above, or other pharmaceutical agents, carriers,adjuvants, etc. Such compound(s) or compositions can be administeredorally, parenterally, either in the form of solid, semi-solid, or liquiddosage forms. Typically, administration is by a pharmaceuticalcomposition containing the pharmaceutically active compound and one ormore pharmaceutical carriers or adjuvants.

The administerable pharmaceutical composition may take the form of oraltablets, vaginal or uterine tablets or suppositories, pills, capsules,liquid solutions, suspensions, or the like, preferably in unit dosageforms suitable for simple administration of precise dosages.Conventional nontoxic solid carriers include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesiumcarbonate, and the like. The active compound as defined above may beformulated as suppositories using, for example, polyalkylene glycols,for example, polypropylene glycol, as the carrier. Liquidpharmaceutically administerable compositions can, for example, beprepared by dissolving, dispersing, etc. an active compound as definedabove and optional pharmaceutical adjuvants in a carrier, such as, forexample, water, saline, aqueous dextrose, glycerol, ethanol, and thelike, to thereby form a solution or suspension. If desired, thepharmaceutical composition to be administered may also contain minoramounts of non-toxic auxiliary substances such as wetting or emulsifyingagents, pH buffering agents and the like, for example, sodium acetate,sorbitan monolaurate, triethanolamine oleate, etc. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easton, Pennsylvania, 14th Edition,1970. The composition or formulation to be administered will, in anyevent, contain a quantity of the active compound(s) in an amounteffective to delay the onset of parturition or to postpone parturitionif uterine contractions have already begun. Generally a daily dose offrom 5 mg. to about 250 mg. of the active compound per kilogram of bodyweight will be administered, with administration being a single dailydose or up to three or four smaller doses regularly given throughout theday. The amount of active compound administered will, of course, dependon its relative activity.

DESCRIPTION OF SPECIFIC EMBODIMENTS

The following specific description, recited in the examples below, isgiven to enable those skilled in this art to more clearly understand andpractice the present invention. It should not be considered as alimitation upon the scope of the invention but merely as beingillustrative and representative thereof.

Where necessary, examples are repeated to prepare additional materialfor later examples; and unless otherwise specified, the reactions arecarried out at room temperature (20° to 30° C.).

EXAMPLE 1

200 G. of nitroterephthalic acid (a) was dissolved in 1 liter ofisopropanol and the thus-obtained solution was saturated with hydrogenchloride and refluxed for 3 days. (During this period, hydrogen chloridewas passed into the solution occasionally in order to maintain theconcentration thereof.) The reaction solution was then cooled and theisopropanol was removed by evaporation under reduced pressure to give aresidue which was dissolved in 500 ml. of methylene chloride. Theresultant solution was washed with 10% aqueous sodium carbonate, and theorganic layer obtained was dried over magnesium sulfate, followed byremoval of the solvent in vacuo to give 245 g. (yield 87.5%) ofdiisopropyl nitroterephthalate (1), an oil; IR: ν_(max).^(CHCl).sbsp.31724, 1542, 1350 cm⁻¹ ; NMR: δ_(TMS) ^(CDCL).sbsp.3 1.35 (6H, d), 1.40(6H, d), 5.24 (1H, 7 lines), 5.27 (1H, 7 lines), 7.71 (1H, d), 8.24 (1H,dd), 8.43 ppm (1H, d).

EXAMPLE 2

5.1 G. of sodium hydride was slowly added to a cooled (-20° C.) solutionof 23.5 ml. of benzyl mercaptan in 100 ml. of dimethylformamide. Theresultant solution was cooled to -30° C. and there was added thereto 53g. of diisopropyl nitroterephthalate (1) in 100 ml. ofdimethylformamide. After one hour at -30° C. and 2 hours at 0° C., thereaction mixture was poured into water, the precipitate was filteredoff, washed with water and dried to yield 77-92% of crudediisopropyl-(benzylthio)-terephthalate (2), a sample of which, followingrecrystallization from pentane, melted at 70°-71° C.

EXAMPLE 3

The crude diisopropyl-(benzylthio)-terephthalate (2) obtained in Example2 was refluxed with 500 ml. methanol, 25 g. of potassium hydroxide and50 ml. of water for 2 hours. The reaction mixture was then concentratedto a small volume, cooled, diluted with water and filtered throughdiatomaceous earth (Celite). The thus-obtained filtrate was acidifiledwith 4N hydrochloric acid and the precipitate which formed was collectedby filtration and dried in an oven at 90°-100° C. to yield 45 g. (87%)of (benzylthio)-terephthalic acid (3) having a melting point of299°-300° C.

EXAMPLE 4

10 G. of (benzylthio)-terephthalic acid (3) was treated with 10 ml. ofthionyl chloride and the reaction mixture was refluxed for 4 hours.After removal of the excess thionyl chloride in vacuo, the residueobtained was slurried with hexane and the solid product was filtered offto yield 10.2 g. (92%) of (benzylthio)-terephthalyl chloride (4) havinga melting point of 158° C.

EXAMPLE 5

10.2 G. of (benzylthio)-terephthalyl chloride (4) in 100 ml. ofmethylene chloride was added to a solution of 14.75 g. of aluminumchloride in 100 ml. of methylene chloride containing 10.51 ml. ofnitromethane. After 5 hours at 25° C., 16.5 ml. of saturated aqueoussodium chloride was added with vigorous stirring. The inorganic saltswhich precipitated were filtered off and the filtrate was evaporated todryness to give a solid residue which was slurried with ether. The etherslurry was filtered to yield 7.0 g. (70.7%) of6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-carbonyl chloride (5) havinga melting point of 119°-120° C.

EXAMPLE 6

A solution of 11 g. of6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-carbonyl chloride (5) in 100ml. of methylene chloride was slowly added to excess diazomethane(prepared from 20 g. N-nitroso N-methylurea) in 200 ml. of ethersolution. After 2 hours the reaction mixture was concentrated to about50 ml. by boiling off the solvent, followed by cooling. The cooledreaction mixture was filtered to yield a residue of 9.5 g. (85%) of3-diazoacetyl-6,11-dihydrodibenzo-[b.e.]-thiepin-11-one (6) having amelting point of 153° C., with decomposition.

EXAMPLE 7

9.5 G. of 3-diazoacetyl-6,11-dihydrodibenzo-[b.e.]-thiepin-11-one (6)was suspended in 500 ml. of methanol and the suspension was stirredvigorously and refluxed. 2 G. of silver benzoate suspended in 20 ml. ofmethanol was added in 2 ml. portions over 50 minutes. The reactionmixture was refluxed for 15 hours, cooled and the solvent removed at thepump and following chromatography of the residue on 400 g. of silica gelthere was obtained 7 g. of methyl6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate (7) having a meltingpoint (ether) of 100°-101° C.

Similarly, by substituting other alkyl alcohols, containing 2 to 12carbon atoms, for methanol, in the procedure of this Example there areobtained, for example,

ethyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate.

propyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate,

isopropyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate,

hexyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate,

nonyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate,

dodecyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate, and thelike.

EXAMPLE 8

7.0 G. of methyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate (7)was stirred with 200 ml. of methanol and a solution of 2.0 g. ofpotassium hydroxide in 5 ml. of water was added. After 1 hour, thesolution was clarified by filtration and the filtrate was acidified with3N aqueous hydrochloric acid and diluted with 400 ml. of water. Theprecipitated solid was filtered off, dried in an oven at about 80° C.and recrystallized from benzene:hexane to yield 5.6 g. of6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid (8) having amelting point of 154°-155° C.

Similarly, 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid isobtained by substituting, in place of methyl6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate, the other 3-estersobtained in Example 7, for example,

ethyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate,

propyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate,

isopropyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate,

hexyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate,

nonyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate,

dodecyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate, and thelike.

EXAMPLE 9

A solution of 2.5 g. of6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-carbonyl chloride (5) in 30ml. of methylene chloride was added to a solution of diazoethane(prepared from 20 g. N-ethyl N-nitrosourea) in 150 ml. of ether at -20°C. The reaction mixture was allowed to warm to room temperature and mostof the solvent was blown off in a stream of nitrogen, followed byfiltration to yield 1.5 g. of3-(α-diazopropionyl)-6,11-dihydrodibenzo-[b.e.]-thiepin-11-one (9)having a melting point of 127° C., with decomposition.

EXAMPLE 10

1.1 G. of 3-(α-diazopropionyl)-6,11-dihydrodibenzo-[b.e.]-thiepin-11-one(9) suspended in 3 ml. of collidine was added to a mixture of 5 ml. ofbenzyl alcohol and 5 ml. of collidine maintained at 170°-175° C. After 5minutes, the reaction mixture was cooled and the solvents were distilledoff in vacuo, followed by chromatography of the residue on silica gel toyield 1.0 g. of benzyl(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3yl) propionate (10),a colorless oil; IR: ν_(max)..sup. CHCl.sbsp.3 1735, 1640, 1600 cm.⁻ ¹ ;NMR: δ_(TMS) ^(CDCl).sbsp.3 1.50 (3H, d), 3.66 (1H, q), 4.0 (2H, s),5.07 (2H, s), 7.0-7.6 (6H, m), 8.10 ppm (1H, dd); MS: 388 (M⁺).

EXAMPLE 11

1.0 G. of benzyl (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionate (10) in 25 ml. of methanol was treated with 0.3 g. ofpotassium hydroxide in 2 ml. of water. After 1 hour, the reactionmixture was poured into 25 ml. of 3N hydrochloric acid and 100 ml. ofwater. The resultant mixture was extracted with ethyl acetate and theorganic layer was then extracted with 10% aqueous sodium carbonatesolution. The basic aqueous layer was acidified with 3N hydrochloricacid and the precipitated acid,(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid,was extracted with ether. The ether layer was evaporated after dryingover magnesium sulfate to yield an oil which was taken up in 5 ml. ofbenzene. The benzene solution was treated with 0.5 g. ofdicyclohexylamine and the solution was allowed to crystallize overnight,followed by drying to yield 640 mg. of dicyclohexylammonium(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate (11)having a melting point of 163°-165° C.

EXAMPLE 12

640 Mg. of dicyclohexylammonium(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate (11)was dissolved in 10 ml. of methylene chloride and the solution wasstirred for 15 minutes with an excess of sodium acid sulfate monohydrate(1.0 g.). The reaction mixture was filtered and the solvent was removedin vacuo. The residue was extracted with ether. Evaporation of the etherextract yielded an oil which on drying under high vacuum (0.1 mm) gave300 mg. of (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid (12), as a foam, having an IR: ν_(max).^(KBr) 3700-2500,1710, 1640 cm.⁻ ¹ ; NMR: δ_(Ims) ^(CDCL) .sbsp.3 1.47 (3H, d), 3.68 (1H,q), 4.00 (2H, s), 7.0-8.0 (6H, m), 8.10 ppm (1H, d); MS: 298 (M⁺).

Dicyclohexylammonium(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate (11)was obtained in several runs according to the procedure described inExample 11. The products obtained from these runs were combined andtreated according to the procedure of Example 12 to yield a foam whichwas crystallized from diethyl ether:hexane (2:1) to yield(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid(12), having a melting point of 113°-115° C., and the same IR, NMR andMS as set forth above in this Example 12.

EXAMPLE 12A

To 4.0 g. of sodium hydride (100%) in 600 ml. of N,N-dimethylacetamide,under a nitrogen atmosphere, there was added 41 g. of methyl6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate (13, R' = methyl), adeep red color developing. The mixture was stirred at room temperatureovernight, followed by the rapid addition of 20.0 g. of methyl iodide.The thus-obtained reaction mixture, which had turned from red togreen-blue, was stirred at room temperature for 15-20 minutes, pouredinto, and shaken with, a mixture of 6 l. of saturated sodium chloridesolution, 600 ml. of water and 2 l. of ethyl acetate. The layers wereallowed to separate and the organic layer was successively washed withthree 300 ml. portions of saturated sodium chloride solution. Thesaturated sodium chloride solution washes were successively extractedwith three 300 ml. portions of ethyl acetate. The ethyl acetate extractswere combined, dried over sodium sulfate and evaporated to dryness undervacuum to yield 46.0 g. of a dark yellow residue comprising methyl(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate (14,R' = methyl), which was combined with 25.0 g. of similar materialpreviously obtained, using the same alkylation procedure. The combinedresidues (71.0 g.) were percolated over 1 kg. of silica gel, followed byelution with methylene chloride and finally with ethyl acetate:methylenechloride (2.98). The eluted fractions which, by thin layerchromatography, predominantly showed the presence of the α-methylatedproduct, were combined, and evaporated to dryness to yield 62.0 g. of amore pure pale yellow powder comprising methyl(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate (14,R' = methyl), [a sample of methyl(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate (14,R' = methyl), obtained by the same procedure, after crystallization fromdiethyl ether had the following physical constants: melting point62.0°-62.5° C.; IR: ν_(max).^(KB).sbsp.r 3700-2500, 1740, 1640 cm.⁻ ¹ ;NMR: δ_(TMS) ^(CDCl) .sbsp.3 1.47 (3H, d), 3.65 (3H, s), 3.68 (1H, q),4.02 (2H, s), 7.0-8.0 (6H, m), 8.21 ppm (1H, d); MS: 312 (M⁺)], whichwas dissolved in a mixture of 1600 ml. of tetrahydrofuran and 800 ml. ofwater. To the thus-obtained solution there was added 180 ml. of 1Nsodium hydroxide and the reaction mixture was stirred for 3 hours,followed by removal of tetrahydrofuran under vacuum, and dilution with 3l. of water. The dilute basic solution was extracted with two 600 ml.portions of ethyl acetate, followed by acidification of the aqueouslayer with 2N hydrochloric acid. The acidified aqueous solution wasextracted several times with methylene chloride. The methylene chlorideextracts were combined, dried over sodium sulfate and evaporated todryness to give a residue which was taken up in 250 ml. of diethyl etherand allowed to crystallize. The fine white crystals which formed werefiltered, washed with ice-cold diethyl ether, and sucked dry to yield40.0 g. of (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid (12), having a melting point of 114.5°-115.5° C.(uncorrected), IR: ν_(max).^(KB).sbsp.r 3700-2500, 1710, 1655 cm.⁻ ¹ ;NMR: δ_(TMS) ^(CDCl) .sbsp.3 1.47 (3H, d), 3.68 (1H, q), 4.00 (2H, s),7.0-8.0 (6H, m), 8.12 ppm (1H, d); MS: 298 (M⁺).

Similarly substituting other 3-esters of6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid, e.g.

ethyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate,

propyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate,

isoamyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate,

hexyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate,

nonyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate,

dodecyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate, and thelike,

for methyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate, isproductive of (dl)-2-6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid.

EXAMPLE 12B

a. 5.0 G. of (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid (12) was dissolved in 50 ml. of benzene containing 5 ml.of thionyl chloride and 3 drops of dimethylformamide and stirred for11/2 hours. The reaction mixture was evaporated to an oily residue whichwas dissolved in 50 ml. of dry benzene and re-evaporated to give an oilyresidue comprising(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionylchloride. This oily residue was dissolved in 250 ml. of acetonitrile and10 ml. of (1)-1-phenylethylamine and 6.5 ml. of triethylamine were addedthereto. After stirring for 2 hours the reaction mixture was added to750 ml. of water and extracted with 400 ml. of ethyl acetate. Thethus-obtained organic extract was washed with 400 ml. of 2N hydrochloricacid, dried and evaporated, to yield a residue which was chromatographedon 400 g. of silica gel, eluting with benzene:ethyl acetate (10:1) toobtain firstly 3.3 g. of the less polar(l)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionyl(l)-1-phenylethylamide, which after recrystallization from ethylacetate:hexane (1:2) had a melting point of 162°-163° C. and an [α]_(D)+16.4° (10 mg./ml., chloroform); and secondly 2.8 g. of the more polar(d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionyl(l)-1-phenylethylamide, which after recrystallization from ethylacetate:hexane (1:2), had a melting point of 170°-171° C. and an [α]_(D)-1.4° (10 mg./ml., chloroform.).

b. 3.0 G. of (d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionyl (l)-1-phenylethylamide in 93 ml. of concentrated hydrochloricacid and 62 ml. of acetic acid was heated for 8 hours at 87° C. Themixture was cooled, poured into water and extracted with 250 ml. ofethyl acetate. The ethyl acetate extract was washed with water andextracted with 250 ml. of 0.5 molar aqueous sodium carbonate. The ethylacetate solution remaining following the aqueous sodium carbonateextraction was dried and evaporated to give 1.06 g. of unchangedphenylethylamide starting material. The aqueous sodium carbonate extractwas acidified with 500 ml. of 2N hydrochloric acid and extracted with350 ml. of ethyl acetate. The ethyl acetate extract was dried andevaporated to give 1.34 g. of a residue comprising2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid. The1.06 g. of recovered phenylethylamide starting material was dissolved in45 ml. of concentrated hydrochloric acid and 30 ml. of acetic acid, andheated for 14 hours at 85° C., followed by working up as described aboveto afford 0.86 g. of a residue comprising2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid whichwas combined with the 1.34 g. obtained above. The combined acid residues(2.2 gm.) were dissolved in 10 ml. of isopropanol and 0.95 gm. of1-amphetamine was added. The solution was cooled to -10° C. and left for4 hours and filtered to yield 2.69 g. of a residue which was shaken with100 ml. of 2N hydrochloric acid and 100 ml. of ethyl acetate. Theseparated organic layer was dried over magnesium sulfate and evaporatedto yield 1.90 g. of a residue which was dissolved in 9 ml. ofisopropanol, followed by the addition of 0.86 g. of 1-amphetamine. Thesolution was cooled to -10° C. and left for 2 hours, followed byfiltration to yield 2.53 g. of a residue which was shaken with 100 ml.of 2N hydrochloric acid and 100 ml. of ethyl acetate. The organic layerwas separated, dried over magnesium sulfate, and evaporated to give 1.80g. of a residue which was dissolved in 8 ml. of isopropanol followed bythe addition of 0.86 g. of 1-amphetamine. The solution was cooled to-10° C. and left for 2 hours, followed by filtration to yield 2.46 g. ofa residue which was shaken with 100 ml. of 2N hydrochloric acid and 100ml. of ethyl acetate. The organic layer was separated, dried overmagnesium sulfate, and evaporated to give 1.75 g. of a residue which wasdissolved in 7 ml. of isopropanol, followed by the addition of 0.83 g.of 1-amphetamine. The solution was cooled to -10° and left for 16 hoursfollowed by filtration, to yield 2.40 g. of a residue which was shakenwith 100 ml. of hydrochloric acid and 100 ml. of ethyl acetate. Theseparated organic layer was washed, dried over magnesium sulfate, andevaporated to give 1.647 g. of(d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid[(12)-(d)-acid isomer], as a gum, having an [α]_(D) + 37.2° (5 mg./ml.,chloroform); NMR: δ_(TMS) ^(CDCl) .sbsp.3 1.48 (3H, d), 3.68 (1H, q),4.01 (2H, s), 7.0-7.6 (6H, m), 8.15 ppm (1H, d), MS: 298 (M⁺) 265, 253.

c. 2.64 G. of (l)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionyl (l)-1-phenylethylamide was dissolved in 21 ml. of acetic acidand 111 ml. of acetic anhydride and the solution cooled to 0° C. 9.25 G.of sodium nitrite was added in 4 portions over 1 hour. The mixture wasstirred at 0° C. for 5 hours and then at room temperature for 17 hours.250 Ml. of water and 100 ml. of ethyl acetate were added and the mixturestirred vigorously for 11/2 hours, followed by dilution with 500 ml. ofwater and extracted with 400 ml. of ethyl acetate. The organic extractwas washed, dried over magnesium sulfate, evaporated and the residueobtained refluxed for 1 hour in 50 ml. of benzene. The benzene solutionwas cooled, washed with 100 ml. of 0.5 molar aqueous potassiumcarbonate, dried over magnesium sulfate, and evaporated. The residuethus-obtained was chromatographed on 100 g. of silica gel, eluting withbenzene, to yield 0.75 g. of(l)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acidl-phenylethanol ester, as an oil; NMR: δ_(TMS) ^(CDCl) .sbsp.3 1.29-1.52(6H, m), 3.68 (1H, q), 4.02 (2H, s), 7.0-7.6 (11H, m), 8.16 ppm (1H, m).0.74 G. of the l-phenylethanol ester was then stirred in 10 ml. ofbenzene and 10 ml. of trifluoroacetic acid for 2 hours. followed by theaddition of 200 ml. of water and extracted with 200 ml. of ethylacetate. The organic extract was washed, dried over magnesium sulfate,and evaporated to give 0.51 g. of(l)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid[(12)-(l)-acid isomer] as a gum, having an [α]_(D) -37.8° (5 mg./ml.,chloroform) and the same NMR and MS set forth for the corresponding(d)-compound [(12)-(d)-acid isomer] in part (b) of this example.

EXAMPLE 13

250 Mg. of 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid (8)was dissolved in 30 ml. of isoamyl alcohol and the solution wassaturated with hydrogen chloride. After 90 minutes, the excess alcoholwas distilled off in vacuo and the residue was purified by preparativethin layer chromatography [silica gel; ethyl acetate:hexane (1:9)] toyield 171 mg. of isoamyl6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate, which aftercrystallization from methylene chloride/hexane had a melting point of91°-92° C.

Likewise other esters, e.g., methyl, ethyl, propyl, isopropyl, hexyl,nonyl, dodecyl, and the like, of6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid (8) are obtainedby substituting other alcohols, e.g., methyl, ethyl, propyl, isopropyl,hexyl, nonyl, dodecyl alcohol and the like, for isoamyl alcohol.

EXAMPLE 14

150 Mg. of (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid (12) was dissolved in five ml. of methanol and thesolution was saturated with hydrogen chloride. After 24 hours, theexcess alcohol was distilled off in vacuo and the residue was purifiedby chromatography on silica gel [eluant:ethyl acetate:hexane (1:8)] toyield 120 mg. of methyl(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate, anoil, having a UV: λ_(max).^(dioxane) 250, 350nm (ε 21,200, 2950); IR:ν_(max).^(CHCl).sbsp.3 1740, 1645, 1600 cm.^(-;) NMR: δ_(TMS)^(CDCl).sbsp.3 1.48 (3H, d), 3.60 (3H, s), 4.0 2H, s), 7.0-7.6 (6H, m),8.10 ppm (1H, dd).

Similarly, substituting the (12)-(d)-acid isomer,(d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid,or the corresponding (12)-(l)-acid isomer, for the (dl)-mixture, isproductive of the methyl ester of(d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid,or the corresponding methyl ester of the (12)-(l)-acid isomer,respectively.

EXAMPLE 15

300 Mg. of (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid (12) was dissolved in 5 ml. of isoamyl alcohol and thesolution was saturated with hydrogen chloride. After 24 hours, theexcess alcohol was distilled off in vacuo and the residue was purifiedby chromatography on alumina to yield 350 mg. of isoamyl(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate, anoil, having a UV: λ_(max).^(CH).sbsp.3OH 245, 350nm (ε 19,700, 2240; IR:ν_(max).^(CHCl).sbsp.3 1730, 1650, 1600 cm.⁻ ¹ ; NMR: δ_(TMS)^(CDCl).sbsp.3 0.80 (6H, d), 1.45 (6H, d + m), 3.70 (2H, m), 4.0 (2H,s), 7.0-7.6 (6H, m), 8.1 ppm (1H, dd).

Likewise other esters, e.g., ethyl, propyl, isopropyl, hexyl, nonyl,dodecyl, and the like, of(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid(12) are obtained by substituting other alcohols, e.g., ethyl, propyl,isopropyl, hexyl, nonyl, dodecyl alcohol, and the like, for isoamylalcohol.

Similarly, by substituting the (12)-(d)-acid isomer,(d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid,or the corresponding (12)-(l)-acid isomer, for the (dl) -mixture, withthe appropriate alcohol there is obtained the isoamyl, ethyl, propyl,isopropyl, hexyl, nonyl, dodecyl, and the like, esters of(d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid,or the corresponding esters of the (12)-(l)-acid isomer, respectively.

EXAMPLE 16

300 Mg. of 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid (8)in 5 ml. of methanol was titrated with 1N methanolic potassium hydroxideto a faint orange color. The color was discharged by the addition ofthree mg. of solid 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-aceticacid. The solvent was evaporated in vacuo and the residue taken up in 2ml. of methanol, followed by precipitation with ether to yield 335 mg.of crude potassium 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetatewhich, after recrystallization from isopropanol, had a melting point of206°-208° C. (dec.)

Likewise other salts, e.g., ammonium and sodium, of6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid (8) are preparedby substituting ammonium hydroxide and sodium hydroxide for potassiumhydroxide.

EXAMPLE 17

150 Mg. of (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid (12) in one ml. of methanol was titrated with 1Nmethanolic potassium hydroxide to a faint orange color. A small amountof solid (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid was added to decolorize the solution. The solvent wasstripped and 5 ml. of toluene was added. The thus obtained toluenesolution was evaporated to dryness to give a solid, which was dried at100° C. in vacuo to yield 158 mg. of potassium(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate,softening at 120° C. and having a melting point of 145°-155° C. Thissolid on exposure to moist air melted and resolidified to yield 175 mg.of the dihydrate of potassium(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate,having a melting point of 88°-90° C.

Likewise other salts, e.g., ammonium and sodium, of(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3yl) propionic acid(12) are prepared by substituting, e.g., ammonium hydroxide and sodiumhydroxide for potassium hydroxide.

Similarly, by substituting the (12)-(d)-acid isomer,(d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid,or the corresponding (12)-(l)-acid isomer, for the (dl)-mixture, withthe appropriate hydroxide, there is obtained the potassium, ammonium,and sodium salts of(d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid,or the corresponding salts of the (12)-(l)-acid isomer, respectively.

EXAMPLE 18

300 Mg. of 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid (8)was dissolved in an excess of 1N aqueous sodium hydroxide and theresultant solution was buffered with 0.3 g. of ammonium chloride. Thebuffered solution was added to a solution of 200 mg. calcium carbonatein 1N aqueous hydrochloric acid. The precipitate which formed wascollected by filtration, washed consecutively with water,dimethoxyethane and ether, to yield 180 mg. of calcium6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate having a meltingpoint of 220°-225° C. (dec.), softens>205° C.).

Likewise magnesium 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetateis prepared by substituting magnesium carbonate for calcium carbonate.

EXAMPLE 19

175 Mg. of (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid (12) in 5 ml. of methanol was titrated with 1N methanolicpotassium hydroxide to a faint orange color, followed by discharging thecolor by the addition of 3 mg. of solid(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid,yielding a solution containing potassium(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate. Asolution of 40 mg. of calcium carbonate dissolved in the minimum amountof 1N hydrochloric acid necessary to effect solution of the calciumcarbonate, was buffered with 100 mg. of solid ammonium chloride,followed by the further addition of 5 ml. of water. The thus obtainedbuffered calcium solution was then added to the solution of potassium(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate toyield a precipitate. The precipitate was collected, washed with waterand dried at room temperature to yield 160 mg. of calcium(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3 -yl) propionate,softening at 150° C. and having a melting point of 160°-165° C.

Likewise magnesium(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate isprepared by substituting magnesium carbonate for calcium carbonate.

Similarly, by substituting the (12)-(d)-acid isomer,(d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid,or the corresponding (12)-(l)-acid isomer, for the (dl)-mixture, withthe appropriate carbonate, there are obtained the calcium and magnesiumsalts of (d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid, or the corresponding salts of the (12)-(l)-acid isomer,respectively.

EXAMPLE 20

200 Mg. of 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid (8)in one ml. of methanol was titrated with 1N methanolic potassiumhydroxide to a faint orange color. A small amount of solid6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid was added todecolorize the solution. The solvent was stripped and the residue wasdissolved in 5 ml. of water. The thus obtained aqueous solution ofpotassium 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate was addedto a solution of 150 mg. of cupric nitrate trihydrate in 5 ml. of water.The precipitate which formed was collected, washed with water and driedin air to yield 200 mg. of copper6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate, sintering at139°-140° C. and having a melting point of 155°-160° C.

EXAMPLE 21

200 Mg. of (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid (12) in 1 ml. of methanol was titrated with 1N methanolicpotassium hydroxide to a faint orange color. A small amount of solid(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acidwas added to decolorize the solution. The solvent was stripped and theresidue was dissolved in 5 ml. of water. The thus obtained aqueoussolution of potassium(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate wasadded to a solution of 150 mg. of cupric nitrate trihydrate in 5 ml. ofwater. The precipitate which formed was collected, washed with water anddried in air to yield 200 mg. of copper(dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate,sintering at 140° C. and having a melting point of 160°-165° C.

Similarly, substituting the (12)-(d)-acid isomer,(d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid,or the corresponding (12)-(l)-acid isomer, for the (dl)-mixture, isproductive of the copper salt of(d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid,or the corresponding copper salt of the (12)-(l)-acid isomer,respectively.

EXAMPLE 22

200 Mg. of 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid (8)in 15 ml. of hot benzene was treated with 60 mg. of isopropylamine. Thesolution was allowed to cool to room temperature and the product wasfiltered off, washed with ether and dried to yield 217 mg. ofisopropylammonium 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetatehaving a melting point of 147°-148° C.

Likewise other salts, e.g., amine salts, such as, diethylamine,ethanolamine, piperidine, tromethamine, choline, and caffeine, of6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid (8) are preparedby substituting each of the respective amines for isopropylamine.

EXAMPLE 23

193 Mg. of (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid (12) in 10 ml. of benzene was treated with 60 mg. ofpiperidine. The solution obtained was allowed to stand for 1 hour andthe crystalline material which formed was filtered, washed with etherand air dried to yield 183 mg. of piperidinium (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate, a sample ofwhich, following recrystallization from benzene had a melting point of140°-141° C.

Likewise other salts, e.g., amine salts, e.g., isopropylamine,diethylamine, ethanolamine, tromethamine, choline, and caffeine, of(dl)-2-(6,11 -dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionate areprepared by substituting each of the respective amines for piperidine.

Similarly, substituting the (12)-(d)-acid isomer, (d)-2-(6,11-dihydrodibenzo-[b.e.]-thienpin-11-one-3-yl) propionic acid, or thecorresponding (12)-(l)-acid isomer, for the (dl)-mixture, with theappropriate amine, is productive of the amine salts, e.g., piperidine,isopropylamine, diethylamine, ethanolamine, tromethamine, choline andcaffeine, of (d)-2-(6,11 -dihydrodibenzo-[b.e.]-thienpin-11-one-3-yl)propionic acid, or the corresponding (12)-(l)-acid isomer amine saltsthereof, respectively.

EXAMPLE 24

One g. of potassium 6,11-dihydrodibenzo-[b.e.]-thienpin-11-one-3-acetate is dissolved in 50 ml.of water and the solution is acidified with 20 ml. of 3N aqueoushydrochloric acid. The reaction mixture is extracted twice with ethylacetate (25 ml. portions) and the extracts are combined, washed with 50ml. of water and dried over magnesium sulfate. The solvent is evaporatedunder reduced pressure and the residue is recrystallized from benzene toyield 6,11 -dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid (8).

Similarly, other salts, e.g., sodium, ammonium, calcium, amine, and thelike, of 6,11 -dihydrodibenzo-[b.e.]-thienpin- 11-one-3-acetic acid areconverted to 6,11 -dehydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid.

In like manner, substituting the salts, e.g., potassium, sodium,ammonium, calcium, amine, and the like, of (dl)-2-(6,11-dihydrodibenzo-]b.e.]-thiepin-11-one-3-yl) propionic acid, (d)-2-(6,11-dihydrodibenzo-[b.e.]-thienpin-11-one-3-yl) propionic acid, and thecorresponding (l)-acid isomer salts thereof, respectively, is productiveof (dl)-2-(6,11 -dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionicacid, (d)-2-(6,11 -dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionicacid, and the corresponding (l)-acid isomer thereof, respectively.

EXAMPLE 25

One g. of methyl 6,11 -dihydrodibenzo-[b.e.]-thienpin-11-one-3-acetate(7) was dissolved in 500 ml. of toluene containing 5 g. of n-octanol and0.5 g. of p-toluenesulfonic acid. The reaction mixture was heated in anitrogen atmosphere and a total of 350 ml. of toluene was slowlydistilled out over a period of 5 hours. The reaction mixture was cooledand concentrated to about 10 ml. by evaporation under reduced pressure.The residue was then chromatographed on 200 g. of silica gel elutingwith hexane:ethyl acetate (1:8) to yield octyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate.

Similarly, other lower esters (e.g., the propyl ester) of 6,11-dihydrodibenzo-[b.e.]-thienpin- 11-one-3-acetic acid can betransesterified to a higher ester (e.g., the decyl ester) of 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid.

In like manner lower ester (e.g., the methyl ester) of (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid, (d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic, or thecorresponding (l)-acid isomer lower esters thereof, are converted to thehigher esters (e.g., the octanyl ester) of (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid, (d)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic, or thecorresponding (l)-acid isomer higher ester thereof, respectively.

EXAMPLE 26

Five hundred mg. of dodecyl6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate was refluxed with250 ml. of absolute ethanol containing 10 mg. of sodium cyanide for 18hours in a nitrogen atmosphere. The reaction mixture was cooled andevaporated under reduced pressure to yield a residue which waschromatographed on 100 g. of silica gel eluting with hexane: ethylacetate (1:8) to yield ethyl 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate.

Similarly, other higher esters (e.g., the nonyl ester) of 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid can betransesterified to a lower ester (e.g., the hexyl ester) of 6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid.

In like manner, higher esters (e.g., the dodecyl ester) of (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid are convertedto the lower esters (e.g., the ethyl ester) of (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid.

EXAMPLE 27

0.05 G. of (l)-2-(6,11 -dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid [(12)-(l)-acid isomer] was refluxed, under nitrogen, in 6ml. of water containing 0.07 g. of sodium hydroxide for 7 hours. Thereaction solution was cooled, acidified with 5 ml. of 2N hydrochloricacid and extracted with 15 ml. of ethyl acetate. The extract was washedwith 15 ml. of water, dried with magnesium sulfate, and evaporated toyield 0.041 g. of (dl)-2-(6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl) propionic acid (12), a gum,having an [α]_(D) - .80 ± 1.0° (5 mg./ml. chloroform); NMR: δ_(TMS)^(CDCl) .sbsp.3 1.47 (3H, d), 3.70 (1H, g), 7.0-7.6 (6H, m,), 8.13 ppm(1H, d); MS 298 (M⁺) 265, 253.

EXAMPLE 28

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        6,11-dihydrodibenzo-[b.e.]-                                                   thiepin-11-one-3-acetic acid                                                                    150                                                         cornstarch         40                                                         sucrose           200                                                         ______________________________________                                    

The above ingredients are thoroughly mixed and pressed into singlescored tablets.

EXAMPLE 29

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        (dl)-2-(6,11-dihydrodibenzo-                                                  [b.e.]-thiepin-11-one-3-yl)                                                   propionic acid    25                                                          cornstarch        100                                                         lactose           393                                                         magnesium stearate                                                                              2                                                           ______________________________________                                    

The above ingredients are mixed intimately and pressed into singlescored tablets.

12.5 Mg. of (d)-2-(6,11 -dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid is substituted for the 25 mg. of the (dl) compound of theabove composition.

EXAMPLE 30

    ______________________________________                                        Ingredients         Quantity per capsule, mgs.                                ______________________________________                                        potassium 6,11-dihydrodibenzo-                                                [b.e.]-thiepin-11-one-3-acetate                                                                   150                                                       lactose             190                                                       ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapusle.

EXAMPLE 31

    ______________________________________                                        Ingredients         Quantity per capsule, mgs.                                ______________________________________                                        calcium 6,11-dihydrodibenzo-                                                  [b.e.]-theipin-11-one-3-acetate                                                                   150                                                       lactose             182                                                       magnesium stearate  8                                                         ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

EXAMPLE 32

    ______________________________________                                        Ingredients         Quantity per tablet, mgs.                                 ______________________________________                                        isopropylammonium 6,11-dihydro-                                               dibenzo-[b.e.]-thiepin-11-one-                                                3-acetate           150                                                       cornstarch          100                                                       lactose             370                                                       magnesium stearate  2                                                         ______________________________________                                    

The above ingredients are mixed intimately and pressed into singlescored tablets.

EXAMPLE 33

    ______________________________________                                        Ingredients        Quantity per capsule, mgs.                                 ______________________________________                                        methyl 6,11-dihydrodibenzo-[b.e.]-                                            thiepin-11-one-3-acetate                                                                         25                                                         lactose            225                                                        ______________________________________                                    

The above ingredients are mixed and introduced into a No. 1 hard-shellgelatin capsule.

EXAMPLE 34

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        6,11-dihydrodibenzo-[b.e.]-                                                   thiepin-11-one-3-acetic acid                                                                    150                                                         sucrose           245                                                         ______________________________________                                    

The above ingredients are thoroughly mixed and processed into singlescored tablets, one tablet being administered every 3 to 4 hours.

EXAMPLE 35

    ______________________________________                                        Ingredients         Quantity per tablet, mgs.                                 ______________________________________                                        isoamyl 6,11-dihydrodibenzo-                                                  [b.e.]-thiepin-11-one-3-acetate                                                                   200                                                       cornstarch          100                                                       lactose             368                                                       magnesium stearate  2                                                         ______________________________________                                    

The above ingredients are mixed intimately and pressed into singlescored tablets.

EXAMPLE 36

    ______________________________________                                        Ingredients       Quantity per capsule, mgs.                                  ______________________________________                                        (dl)-2-(6,11-dihydrodibenzo-                                                  [b.e.]-thiepin-11-one-3-yl)                                                   propionic acid    25                                                          lactose           225                                                         detrose           10                                                          ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

12.5 Mg. of (d)-2-(6,11 -dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid is substituted for the 25 mg. of the (dl) compound of theabove composition.

EXAMPLE 37

    ______________________________________                                        Ingredients       Quantity per capsule, mgs.                                  ______________________________________                                        methyl 6,11-dihydrodibenzo-                                                   [b.e.]-thiepin-11-one-3-                                                      acetate           150                                                         lactose           99                                                          ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

EXAMPLE 38

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        isoamyl 6,11-dihydrodibenzo-                                                  [b.e.]-thiepin-11-one-3-                                                      acetate           200                                                         lactose           135                                                         magnesium stearate                                                                              5                                                           ______________________________________                                    

The above ingredients are mixed and pressed into single tablets.

EXAMPLE 39

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        calcium 6,11-dihydrodibenzo-                                                  [b.e.]-thiepin-11-one-3-                                                      acetate             150                                                       cornstarch (paste)  50                                                        magnesium stearate  0.8                                                       lactose             to 500                                                    ______________________________________                                    

The above ingredients are thoroughly mixed and pressed into singlescored tablets.

EXAMPLE 40

    ______________________________________                                        Ingredients       Quantity per tablet, mgs.                                   ______________________________________                                        potassium 6,11-dihydrodibenzo-                                                [b.e.]-thiepin-11-one-3-acetate                                                                   125                                                       cornstarch          38                                                        magnesium stearate  0.76                                                      polyvinylpyrrolidone                                                                              17                                                        lactose             to 380                                                    ______________________________________                                    

The above ingredients are mixed intimately and pressed into singlescored tablets.

EXAMPLE 41

    ______________________________________                                        Ingredients        Quantity per capsule, mgs.                                 ______________________________________                                        isopropylammonium 6,11-dihydrodi-                                             benzo-[b.e.]-thiepin-11-one-3-                                                acetate              250                                                      cornstarch           38                                                       lactose              to 380                                                   ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

EXAMPLE 42

    ______________________________________                                        Ingredients         Quantity per capsule, mgs.                                isoamyl 6,11-dihydrodibenzo-                                                  [b.e.]-thiepin-11-one-3-acetate                                                                   300                                                       lactose             72                                                        magnesium stearate  8                                                         ______________________________________                                    

The above ingredients are mixed and introduced into a hard-shell gelatincapsule.

EXAMPLE 43

An injectable preparation buffered to a pH of 8.5 is prepared having thefollowing composition:

    ______________________________________                                        (dl)-2-(6,11-dihydrodibenzo-                                                  [b.e.]-thiepin-11-one-3-yl                                                    propionic acid         0.2 g                                                  K.sub.2 HPO.sub.4 buffer (0.4 M solution)                                                            2 ml.                                                  KOH (1N)               8.6 ml.                                                water (sterile)      to 20 ml.                                                ______________________________________                                    

0.1 G. of (d)-2-(6,11 -dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid is substituted for the 0.2 g. of the (dl) compound of theabove composition.

EXAMPLE 44

A suppository totaling 2.8 grams is prepared having the followingcomposition:

    ______________________________________                                        (dl)-2-(6,11-dihydrodibenzo-                                                  [b.e.]-thiepin-11-one-3-yl                                                    propionic acid          25 mg.                                                Witepsol H-15                                                                 (triglycerides of saturated                                                   vegetable fatty acids; a                                                      product of Riches-Nelson, Inc.,                                               New York, N.Y.)         balance                                               ______________________________________                                    

12.5 Mg. of (d)-2-(6,11 -dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid is substituted for the 25 mg. of the (dl) compound of theabove composition.

EXAMPLE 45

An oral suspension for pediatric use is prepared having the followingcomposition:

    ______________________________________                                        (dl)-2-(6,11-dihydrodibenzo-                                                  [b.e.]-thiepin-11-one-3-yl)                                                   propionic acid    0.25 g.                                                     fumaric acid      0.5 g                                                       sodium chloride   2.0 g.                                                      methyl paraben    0.1 g.                                                      granulated sugar  25.5 g.                                                     sorbitol (70% solution)                                                                         12.85 g.                                                    Veegum K (Vanderbilt Co.)                                                                       1.0 g.                                                      flavoring         0.035 ml.                                                   colorings         0.5 mg.                                                     distilled water   to 100 ml.                                                  ______________________________________                                    

0.125 G. of (d)-2-(6,11 -dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid is substituted for the 0.25 g. of the (dl) compound ofthe above composition.

EXAMPLES 46-47

Powdered top dressings for veterinary use are prepared having thefollowing compositions:

    ______________________________________                                                           Ex. 46 Ex. 47                                              ______________________________________                                        (dl)-2-(6,11-dihydrodibenzo-                                                  [b.e.]-thiepin-11-one-3-yl                                                    propionic acid       0.2 g.   0.4 g.                                          sucrose              5.7 g.   3.7 g.                                          polyvinyl pyrrolidone                                                                              0.3 g.   0.3 g.                                          ______________________________________                                    

0.1 G. of (d)-2-(6,11 -dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid is substituted for the 0.2 g. of the (dl) compound of thecomposition of Example 46.

0.2 G. of (d)-2-(6,11 -dihydrodibenzo-[b.e.]-thiepin-11-one-3-yl)propionic acid is substituted for the 0.4 g. of the (dl) compound of thecomposition of Example 47.

EXAMPLE 48

A suppository totaling 2.8 grams is prepared having the followingcomposition:

    ______________________________________                                        6,11-dihydrodibenzo-[b.e.]-                                                   thiepin-11-one-3-acetic acid                                                                          275 mg.                                               Witepsol H-15           balance                                               ______________________________________                                    

EXAMPLE 49

Several tests were run which simultaneously evaluated

a. phenylbutazone,

b. 6,11 -dihydrodibenzo-[b.e.]-thiepin-11-one-2-acetic acid,

c. 6,11 -dihydrodibenzo-[b.e.]-oxepin-11-one-3-acetic acid, and

d. 6,11 -dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid,

for oral anti-inflammatory activity, utilizing carrageenin induced pawinflammation in the rat, after the method of Winter et al., Proceedingsof the Society for Experimental Biology and Medicine, Vol. 111, page544-547 (1962), as follows: Materials and Methods -- Female ratsweighing 80-90 grams are used. The test materials are given at hour 0orally by gavage in 1 ml. aqueous vehicle. At hour 1, 0.05 ml. of a 1%solution (in 0.9% NaCl) of carrageenin is injected into the right hindpaw. This injection causes an inflammation of the paw. The rats aresacrificed at hour 4, at which time both hind paws are removed andweighed separately.

End point: % increase in paw size calculated as follows: ##EQU1##

The data obtained, from the several tests which were run tosimultaneously evaluate the compounds, was analyzed according tostandard statistical procedures and the results of such analysis were asfollows:

                  TABLE I                                                         ______________________________________                                        Oral Anti-Inflammatory Activity of Compounds (b), (c)                         and (d) Relative To Phenylbutazone, Compound (a)                                                  Anti-Inflammatory                                         Compound            Activity                                                  ______________________________________                                        (a) phenylbutazone  1                                                         (b) 6,11-dihydrodibenzo-[b.e.]-                                               thiepin-11-one-2-acetic acid                                                                      0.25                                                      (c) 6,11-dihydrodibenzo-[b.e.]-                                               oxepin-11-one-3-acetic acid                                                                       12                                                        (d) 6,11-dihydrodibenzo-[b.e.]-                                               thiepin-11-one-3-acetic acid                                                                      54                                                        ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        Oral Anti-Inflammatory Activity of Compound (d)                               Compared Directly To Compound (b)                                                                 Anti-Inflammatory                                         Compound            Activity                                                  ______________________________________                                        (b) 6,11-dihydrodibenzo-[b.e.]-                                               thiepin-11-one-2-acetic acid                                                                      1                                                         (d) 6,11-dihydrodibenzo-[b.e.]-                                               thiepin-11-one-3-acetic acid                                                                      190                                                       ______________________________________                                    

                  TABLE III                                                       ______________________________________                                        Oral Anti-Inflammatory of Compound (d)                                        Compared Directly To Compound (c)                                                                 Anti-Inflammatory                                         Compound            Activity                                                  ______________________________________                                        (c) 6,11-dihydrodibenzo-[b.e.]-                                               oxepin-11-one-3-acetic acid                                                                       1                                                         (d) 6,11-dihydrodibenzo-[b.e.]-                                               thiepin-11-one-3-acetic acid                                                                      3.4                                                       ______________________________________                                    

While the present invention has been described with reference tospecific embodiments thereof, it should be understood by those skilledin this art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material or composition of matter, process,process step or steps, or then-present objective to the spirit of thisinvention without departing from its essential teachings.

What is claimed is:
 1. A compound of the formula: ##STR7## wherein R ishydrogen, an alkyl group containing from one to twelve carbon atoms, ora pharmaceutically acceptable salt thereof when R is hydrogen.
 2. Thecompound of claim 1 wherein R is hydrogen,6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetic acid.
 3. The compoundof claim 1 wherein R is methyl, methyl6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate.
 4. The compound ofclaim 1 wherein R is isoamyl, isoamyl6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate.
 5. The sodium saltof the compound of claim 1, sodium6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate.
 6. The potassiumsalt of the compound of claim 1, potassium6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate.
 7. The calcium saltof the compound of claim 1, calcium6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate.
 8. The copper saltof the compound of claim 1, copper6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate.
 9. Theisopropylammonium salt of the compound of claim 1, isopropylammonium6,11-dihydrodibenzo-[b.e.]-thiepin-11-one-3-acetate.
 10. A compositionfor treating inflammation, pain or pyrexia in mammals consistingessentially of a pharmaceutically acceptable non-toxic excipient and atherapeutically effective amount of a compound represented by theformula: ##STR8## wherein R is hydrogen, an alkyl group containing fromone to 12 carbon atoms, or a pharmaceutically acceptable salt thereofwhen R is hydrogen.
 11. A method of treating inflammation, pain orpyrexia in mammals which comprises administering to a mammal sufferingtherefrom a therapeutically effective amount of a compound representedby the formula: ##STR9## wherein R is hydrogen, an alkyl groupcontaining from one to 12 carbon atoms, or a pharmaceutically acceptablesalt thereof when R is hydrogen.
 12. A composition for administration toa pregnant mammal to delay the onset of parturition consistingessentially of a pharmaceutically acceptable non-toxic excipient and atherapeutically effective amount of a compound represented by theformula: ##STR10## wherein R is hydrogen, an alkyl group containing fromone to 12 carbon atoms, or a pharmaceutically acceptable salt thereofwhen R is hydrogen.